For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) minimal diffusion in the brain severely limits drug distribution after direct drug administration in to brain parenchyma. We systemically investigated convection, molecular transport with bulk flow of fluid, to enhance the distribution of large and small molecules, indium 111-transferrin (In 111-Tf; MW 80,000) and C14-sucrose (MW 359), by maintaining a pressure gradient during interstitial infusion to generate bulk flow through the brain interstitium. The volume of distribution (V-d) containing equal to or greater than 1% of infusate concentration increased linearly with the infusion volume (V-i) for In 111-Tf(V-d/V-i = 6.1) and C14-sucrose (V-d/V-i = 14.1). 24 hr after infusion, the distribution of In 111-Tf increased, became more homogeneous, and penetration into gray matter occurred. By using convection to supplement simple diffusion, greatly enhanced distribution of large and small molecules can be achieved in the brain while achieving drug exposure orders of magnitude greater than systemic exposure.